Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany.
Int J Obes (Lond). 2011 Jun;35(6):762-72. doi: 10.1038/ijo.2010.212. Epub 2010 Oct 12.
Pigment epithelium-derived factor (PEDF) is a multifunctional protein with neurotrophic and anti-angiogenic properties. More recently it became evident that PEDF is upregulated in patients with type 2 diabetes and also contributes to insulin resistance in mice. During characterization of the secretome of in vitro differentiated human adipocytes by two-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization-MS, we found that PEDF is one of the most abundant proteins released by adipocytes. The aim of this study was to investigate the regulation and autocrine function of PEDF in human adipocytes and to determine its paracrine effects on human skeletal muscle cells (hSkMC) and human smooth muscle cells (hSMC).
Human primary adipocytes secrete 130 ng ml(-1) PEDF over 24 h from 1 million cells, which is extremely high as compared with adiponectin, interleukin-6 (IL-6) or IL-8. This release of PEDF is significantly higher than from other primary cells, such as adipose-tissue located macrophages (50-times), hSkMC and hSMC (5-times). PEDF protein expression significantly increases during adipogenesis, which is paralleled by increased PEDF secretion. Furthermore, tumor necrosis factor-α and hypoxia significantly downregulate PEDF protein levels. PEDF secretion was significantly reduced by troglitazone and hypoxia and significantly increased by insulin. Treatment of adipocytes and hSkMC with PEDF induced insulin resistance in adipocytes, skeletal and smooth muscle cells at the level of insulin-stimulated Akt phosphorylation, which was dose dependent and more prominent in adipocytes. Furthermore, inflammatory nuclear factor-κB (NF-κB) signaling was induced by PEDF. In hSMC, PEDF induced proliferation (1.7-fold) and acutely activated proliferative and inflammatory signaling pathways (NF-κB, p38 mitogen-activated protein kinase and mammalian target of rapamycin).
PEDF is one of the most abundant adipokines and its secretion is inversely regulated by insulin and hypoxia. PEDF induces insulin resistance in adipocytes and hSkMC and leads to inflammatory signaling in hSMC. Because of these diverse actions, PEDF is a key adipokine, which could have an important role in diabetes and obesity-related disorders.
色素上皮衍生因子（PEDF）是一种具有神经营养和抗血管生成特性的多功能蛋白。最近的研究表明，PEDF 在 2 型糖尿病患者中上调，并且在小鼠中也有助于胰岛素抵抗。在通过二维聚丙烯酰胺凝胶电泳和基质辅助激光解吸/电离-MS 对体外分化的人脂肪细胞的分泌组进行表征时，我们发现 PEDF 是脂肪细胞释放的最丰富的蛋白质之一。本研究的目的是研究 PEDF 在人脂肪细胞中的调节和自分泌功能，并确定其对人骨骼肌细胞（hSkMC）和人平滑肌细胞（hSMC）的旁分泌作用。
人原代脂肪细胞从 100 万个细胞中在 24 小时内分泌 130ng/ml 的 PEDF，与脂联素、白细胞介素-6（IL-6）或白细胞介素-8（IL-8）相比，这一释放量极高。这种 PEDF 的释放量明显高于其他原代细胞，如脂肪组织中巨噬细胞（高 50 倍）、hSkMC 和 hSMC（高 5 倍）。在脂肪生成过程中，PEDF 蛋白表达显著增加，同时 PEDF 分泌增加。此外，肿瘤坏死因子-α和缺氧显著下调 PEDF 蛋白水平。罗格列酮和缺氧显著降低 PEDF 分泌，胰岛素则显著增加 PEDF 分泌。用 PEDF 处理脂肪细胞和 hSkMC 可诱导脂肪细胞、骨骼肌和平滑肌细胞的胰岛素抵抗，其程度与胰岛素刺激的 Akt 磷酸化水平相关，且在脂肪细胞中更为明显。此外，PEDF 诱导核因子-κB（NF-κB）炎症信号。在 hSMC 中，PEDF 诱导增殖（增加 1.7 倍）并急性激活增殖和炎症信号通路（NF-κB、p38 丝裂原活化蛋白激酶和哺乳动物雷帕霉素靶蛋白）。
PEDF 是最丰富的脂肪因子之一，其分泌受胰岛素和缺氧的反向调节。PEDF 诱导脂肪细胞和 hSkMC 胰岛素抵抗，并导致 hSMC 炎症信号。由于这些不同的作用，PEDF 是一种关键的脂肪因子，它可能在糖尿病和肥胖相关疾病中发挥重要作用。
